The circadian clock is our intrinsic timer where the hypothalamic suprachiasmatic nuclei (SCN) serves as a central pacemaker to orchestrate cell-autonomous oscillators throughout the body. The clock plays fundamental roles in driving rhythmic tissue and systemic functions such as cognition and sleep. Dysregulated physiological rhythms, including sleep/wake cycles, are increasingly appreciated as a key pathophysiological factor associated with Alzheimer's disease (AD). Disruption of the circadian clock has been shown to cause abnormal gene expression and neurodegeneration, and recent studies indicated adverse impact on amyloid dynamics in mice lacking the core clock component BMAL1. However, whether and by what cellular and molecular mechanisms the circadian clock contributes to AD pathology and disease progression remains poorly understood. We previously generated two circadian reporter mouse lines, Per2::Luc and Per2::LucSV, corresponding to normal and enhanced circadian oscillation respectively. Combining this powerful reagent set with single-cell bioluminescence imaging, we propose to test the central hypothesis that there is a functional crosstalk between circadian oscillators in the brain and AD pathology, and enhancing circadian oscillation can decelerate disease progression via regulation of gene expression and protein aggregation. We propose two specific aims. In Aim 1, we will determine a reciprocal relationship between brain clocks and AD progression. We will first address the question whether AD progression dysregulates SCN oscillators using Per2::Luc/APP-PS1 mice as a model of early-onset familial AD expressing a circadian reporter. We will perform single-cell bioluminescence imaging to determine a possible AD-induced deterioration in individual oscillators and coupling in the SCN, as well as phase relationship between SCN and cortex/hippocampus oscillators. Using an environmental jet-lag paradigm to disrupt the light input pathway to the SCN and consequently circadian rhythms, we will investigate whether circadian disruption in turn exacerbates disease progression. In Aim 2, we will address the hypothesis that activation of the oscillator can be deployed as an interventional strategy against AD. Using Per2::LucSV/APP- PS1 mice, we will determine whether enhanced circadian oscillation ameliorates AD behavior and Abeta and tau pathology and sustains robustness in circadian behavioral and sleep architecture. We will further determine the effects of circadian enhancement on putative clock-controlled AD genes. The innovations of this project include a novel conceptual framework of the circadian oscillator as a modifiable causal factor against AD, the new methodologies including Per2::LucSV and single-cell bioluminescence imaging, the interventional strategy of activating the oscillator to delay AD progression, and the elucidation of new molecular and cellular mechanisms linking the circadian oscillator and AD. The studies may ultimately lead to a new paradigm of targeting circadian machinery to improve neuropathological and behavioral deficits in AD and blunt disease progression.